Revised September 2017
Closed Session - May 2nd
- Call to Order - Nora Volkow, M.D. Director, NIDA
- Review of Policy and Procedures - Susan Weiss, Ph.D., Executive Secretary, National Advisory Council on Drug Abuse, Director, Division of Extramural Research, NIDA
Council Review of Grant Applications - Nora Volkow, M.D. Director
- Division of Therapeutics and Medical Consequences (DTMC) - Ivan Montoya, M.P.H., M.D., Acting Director
- Division of Neuroscience and Behavioral (DNB) - Roger Little, Ph.D., Acting Director
- Division of Epidemiology, Services, and Prevention Research (DESPR) - Carlos Blanco, M.D., Ph.D., Director
- Update on Tobacco Industry Funding Issue - Susan Weiss, Ph.D., Director, Division of Extramural Research
- End of Closed Session
Open Session - May 2nd
- Opening and Welcome New Members - Nora Volkow, M.D. Director, NIDA
- NIDA Director's Report - Nora Volkow, M.D., Director, NIDA
- Council Discussion - Council Members
- Lunch Break
Briefing on NASEM Marijuana Report:
Background, Methods & Therapeutic Benefits - Sean Hennessy, Pharm.D., Ph.D., Professor of Epidemiology in Biostatistics and Epidemiology, University of Pennsylvania
Adverse Effects & Recommendations - Sachin Patel, M.D., Ph.D., James G. Blakemore, Chair and Associate Professor of Psychiatry & Behavioral Sciences;
Associate Professor of Molecular Physiology & Biophysics and Pharmacology, Vanderbilt University
- The Biomedical Research Workforce: Supporting More Investigators Sustainability and Efficiently - Michael Lauer, M.D.,Deputy Director, Extramural Research, NIH, and Jon Lorsch, Ph.D., Director, NIGMS
- Concept Clearances - NIDA Staff
- Public Comments
Minutes - May 2nd
The National Advisory Council on Drug Abuse convened its 126th meeting at 9:00 a.m. on May 2, 2017 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland. The closed portion of the meeting held on May 2nd was for the purpose of reviewing applications for Federal grant assistance and was open only to Council members and Federal employees. The open portion, which was open to the public on May 2nd, began at 10:45 a.m. and was also webcast. The Council adjourned on May 2, 2017 at 4:17 p.m
Council Members Present
Judith Auerbach, Ph.D.
Julie Blendy, Ph.D.
John Carnevale, Ph.D.
Linda Chang, M.D.
H. Westley Clark, M.D., J.D.
Arthur Dean, M.A.
Karl Deissesroth, M.D., Ph.D.
Marie Gallo Dyak
Jay Giedd, M.D.
Kenneth Mackie, M.D.
Lisa Marsch, Ph.D.
Edward Nunes, M.D.
Robert Rancourt, J.D.
Steffanie Strathdee, Ph.D.
Eric Verdin, M.D.
Council Members Absent
Anne Andorn, M.D.
Laura Bierut, M.D.
Nora Volkow, M.D.
Susan Weiss, Ph.D.
Federal Employees Present
Will M. Aklin, Ph.D.
Roger Little, Ph.D.
Members of the Public Present
Jennifer Cohen—The National Academies of Sciences, Engineering & Medicine (NASEM)
Sheila Harley—Harley Business Group, LLC
Estelle Ntowe—Kelly Services, Inc.
Dena Procaccini—Kelly Services, Inc.
Ann Rea—Kelly Services, Inc.
Juli Rose—A. Bright Idea, LLC
Jen Sizemore—A. Bright Idea, LLC
Albert Terrillon—Community Anti-Drug Coalitions of America (CADCA)
Roy Walker—Synergy Enterprises, Inc.
Lori Whitten—Synergy Enterprises, Inc.
Patrick Zickler—The Palisades Group, LLC
Closed Portion of the Meeting – May 2, 2017
Call to Order
This portion of the meeting was closed to the public in accordance with sections 552b(c) (4) and 552b(c) (6), Title 5, U.S. Code and section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).
Dr. Nora Volkow, Director, NIDA, called the meeting to order and welcomed the Council and staff. She reminded those present that the Federal Advisory Committee Act applies to Council meetings and that this portion of the meeting was closed to the public.
Dr. Susan Weiss, Executive Secretary, summarized relevant NIH policies, provided detailed instructions on Council review procedures, and reminded those present about NIH confidentiality and conflict of interest policies.
In turn, the Director or a designee for the Division of Therapeutics and Medical Consequences, the Division of Neuroscience and Behavior, and the Division of Epidemiology, Services and Prevention Research presented their applications for consideration by the Council. For each, Council provided concurrence with the initial scientific reviews en bloc. Council also approved Administrative Supplements. Relevant applications were presented to Council for Special Council Review, and Council agreed with program assessments. All Trans-NIH Initiatives, i.e., Common Fund applications and NIDA Secondary applications also received Council concurrence.
Members must absent themselves from the Council meetings during discussion of, and voting on, individual applications from their own institutions or other applications in which there is a conflict of interest, real or apparent. Conflicts of interest statements were signed by each member of the Council. Members were not required to leave if an application in conflict with that member was acted upon en bloc.
Tobacco Industry Funding
A brief update was presented by Dr. Susan Weiss concerning conflicts of interest posed by tobacco industry funding of specific research applicants.
Open Portion of the Meeting – May 2, 2017
Call to Order
Dr. Nora Volkow, Director, NIDA, called the open portion of the meeting to order and welcomed all attendees. She reminded the Council and audience that the meeting was open to the public in compliance with the Government in the Sunshine Act and indicated that time would be provided for public comment.
She then called attention to future Council meetings: May 3, 2017 (CRAN Joint Meeting), September 6, 2017, and February 6, 2018.
Consideration of the Minutes of Council
The Minutes of the NIDA February 2017 meeting were unanimously approved as written.
NIDA Director’s Report – Nora Volkow, M.D., Director, NIDA
Dr. Volkow began by welcoming Dr. Rita Valentino, newly appointed Director of the Division of Neuroscience and Behavior. Dr. Valentino was the Director of the Stress Neurobiology Division, Department of Anesthesiology at Children’s Hospital of Philadelphia. She was also Professor of Anesthesiology and Critical Care at the University of Pennsylvania School Of Medicine. Her research focused on the effects of social stress throughout development, the impact of coping style on behavioral and cognitive health, and substance use and sex differences in response to stress.
She briefly updated Council members on the status of hiring a director of the Division of Therapeutics and Medical Consequences (DTMC); however, due to the continued hiring freeze, the search committee has not begun to recruit the ideal candidate: one who has expertise in pharmacology or neuroscience, and medication development.
The next topic was an update on the budget, which continues to be under a Continuing Resolution, and thus the same as presented at the February 15, 2017 Council meeting. NIDA’s fiscal year (FY) 2017 operating budget is the same FY 2016, at a little over $1 billion, with the AIDS allocation at approximately one third of the total budget. The President’s 2018 NIH Budget Request’s House Hearing is scheduled for May 17, and the Senate Hearing is scheduled for June 22, 2017. Dr. Volkow has been asked to participate in both hearings, reflecting the importance of better understanding substance use disorders, especially in light of the opioid crisis that is affecting the nation.
Turning to what is new at NIH, Dr. Volkow highlighted some of the contributions already made by the BRAIN Initiative. The first five years emphasize technology development, and the second five years will emphasize discovery driven science. The goal is to elucidate circuit structure and function to understand how the brain works, how to manipulate circuits for improved function, and discover what circuits cause brain disorders. This will make circuit abnormalities the basis of diagnostics, and normalization of circuit function the target of intervention. 30 Funding Opportunity Announcements will be published in FY 2017: Four on cell phenotyping: classifying human and non-human brain cells, building a mouse brain atlas, and establishing associated data centers; two on post-doctoral training and career enhancement; three on informatics infrastructure; two to support SBIR and STTR; one on ethical issues in human brain research and neuro-technologies; four on integrated, interdisciplinary research on circuit function; twelve FOAs will be re-issued from FY 2016 on imaging and non-invasive neuro-modulation in humans, and technology development across scales; and lastly, a BRAIN Public-Private Partnership Program for investigators and manufacturers of novel neural stimulation and/or recording devices.
Dr. Volkow then highlighted The National Academies of Sciences, Engineering and Medicine (NASEM, formerly the Institute of Medicine) report “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”, which was released on January 12, 2017. The purpose of the report is to provide a comprehensive review of the current evidence regarding the health effects of cannabis and cannabis-derived products. It included recommendations to address research gaps, improve research quality, improve surveillance, and address research barriers. A review of this report will be presented to Council in the afternoon session.
She then provided an ABCD Study update. Since its launch in September 2015, the ABCD Consortium has recruited 2,302 children, and has announced a Fast Track Data release for spring 2017. This inaugural data release contains unprocessed neuroimaging data from 2000 participants, aged 9-10 years old, as well as basic participant demographics (age, sex), including: high-resolution structural data (3D T1 and T2-weighted scans); advanced diffusion MRI (multiple b-values and directions); resting state fMRI; task fMRI (monetary incentive delay, stop-signal, and emotional N-back), along with raw E-Prime task files. Dr. Gaya Dowling, Director of the ABCD Study, will provide a detailed update at tomorrow’s Collaborative Research on Addiction at NIH (CRAN) Joint National Advisory Council meeting.
Dr. Volkow also presented recommendations from the National Advisory Council on Drug Abuse (NACDA) Tobacco Industry Funding Workgroup. The workgroup is made up of a combination of NIDA Advisory Council members, NIDA and NCI staff. NIDA sought guidance on: 1) Tobacco industry funding of investigators: recommend principles and guidelines for funding decisions involving applicants with financial support from tobacco industry. And 2) data access and data repositories: open access databases for studies such as PATH and ABCD. The group’s recommendations were to ensure that: the applicant’s affiliated institution has a demonstrated independent infrastructure for managing conflicts of interest; the investigators have complete freedom to publish their results; and funds from the industry should not be used to support any NIDA or NIH funded projects (and vice versa). The workgroup did not recommend any special precautions be taken for open access Data repositories, which may include unlimited data (e.g., from surveys) and limited data (e.g. bio specimens), although NIDA could post a statement conveying expectations that the data will be used to benefit public health. In addition, bio specimen collection supported by tobacco industry would be acceptable for NIDA repositories, provided they were collected in an ethical manner (with IRB approval) and appropriate consent.
Dr. Volkow then spoke about three priorities of the new Department of Human Health and Services Secretary, Dr. Thomas Price, which are: the opioid crisis, childhood obesity, and accessibility to mental health services. Dr. Francis Collins, NIH Director, has also embraced elevation of the issue of substance use disorder and using research to end the opioid crisis and NIH is developing a Opioid Research Initiative. The three major components include: improved pain management, by developing safe and more effective strategies; treatment of opioid addiction with new medications and technologies; and overdose reversal by improving access to interventions that reduce mortality and improve linkage to treatment.
A series of three cutting edge scientific meetings to end the opioid crisis have been scheduled and will be led by NIDA and NINDS (pain) with participation of the FDA and industry partners. The first meeting will be held on June 5, 2017 on Medications Development for Opioid Use Disorders and for Overdose Prevention and Reversal. The goal is to stimulate innovative directions in preventing and treating opioid use disorders and overdoses. Key meeting topics will include, opioid-based targets, non-opioid-based targets, biologics (vaccines, monoclonal antibodies), overdose treatment, and the challenges posed by synthetic opioids. The second meeting, Development of Safe, Effective, Non-Addictive Pain Treatments will be held on June 16, 2017 to expedite the screening and development of promising agents with little or no potential for misuse or addiction to treat chronic pain. Key topics for this meeting will be: molecular libraries for screening analgesics, novel or re-purposed agent profiles and mechanisms of action, new analgesic development, genetic data on pain sensitivity, and other treatment modalities. The last meeting in this series will be held on July 7, 2017, focused on understanding the neurobiological mechanisms of pain to accelerate the development of novel pain treatments. The key topics will be pain neural circuitry and maladaptive plasticity, pain and immune function, acute-to-chronic pain transition, and heterogeneity of pain syndromes.
Dr. Volkow presented a new NIDA Opioid Research Funding Opportunity Announcement: Expanding Medication Assisted Treatment (MAT) for Opioid Use Disorders (OUD) in the context of the SAMHSA’s Opioid State Targeted Response (STR) Grants. The goal of this FOA (R21/R33: RFA-DA-18-005) is to solicit applications proposing approaches for expanding MAT for OUD in the general health care sector or linking individuals who received naloxone for the reversal of overdose to MAT in the context of states’ plans for use of funds authorized under the 21st Century Cures Act. This FOA falls under NIDA’s Treatment Interventions priority area.
In addition, as part of NIDA’s public-private partnership, along with support from the Veterans Affairs agency, NIDA has been working with US WorldMeds to evaluate the use of lofexidine for mitigation of opioid withdrawal, and facilitation of opioid discontinuation treatment. The final submission of the New Drug Application (NDA) is targeted for October 2017, with a target approval by May 2018.
Dr. Volkow then moved to another NIDA priority area, HIV and Drugs. She highlighted the 2017 Avant-Garde Awards for HIV/AIDS Research. Three outstanding investigators were recipients: 1) Michael Frazan, Ph.D., from the Scripps Research Institute. His project: A safety switch for an effective HIV-1 vaccine, will use preclinical models to explore safe and effective gene therapies for the long-term prevention of HIV infection in high-risk populations, such as IDU; 2) Eric M. Poeschla, Ph.D., at the University of Colorado, Denver. His project: Novel approaches to innate immunity against HIV-1 and other co-infection viruses, will use animal and human cells to explore the use of viral RNA-dependent RNA polymerase (RdRP) to enhance broad-spectrum (innate) immunity against various viruses, including HIV-1; and 3) Dr. Peter S. Kim, Ph.D. at Stanford University. His project: Making the HIV-1 gp41 pocket amenable to small-molecule drug discovery will employ a strategy that alters the HIV-1 gp41 region, thereby increasing structural rigidity in this region. This will enhance testing of new therapeutics that target the gp41 pocket to prevent HIV infection.
NIDA has recently re-released two new Funding Opportunity Announcements (FOAs) relating to HIV/AIDS. The first is Advancing Exceptional Research on HIV/AIDS and Substance Abuse (R01): RFA-DA-18-002. This FOA will solicit innovative research projects that have the potential to open new areas of HIV/AIDS research and/or lead to new avenues for prevention and treatment of HIV/AIDS in SUD. The nexus with drug abuse has to be clearly described. The second is the NIDA Avant-Garde Award Program for HIV/AIDS and Drug Use Research (DP1): RFA-DA-18-001, which solicits innovative, basic research that may lead to improved prevention, treatment and outcomes; and creative approaches to eradicating HIV or improving the lives of those living with HIV.
Another viral infection that is associated with Injection Drug Use (IDU), is Hepatitis C (HCV). Studies by the National Notifiable Diseases Surveillance System and the CDC have shown increases in the reported number of acute HCV infections in the U.S. since 2009. The main source of HCV infection is IDU, with a surge of HCV in young (18-25 years old) IDUs. However, despite multiple studies, such as the ones by Metzger et al., J.AIDS 2015, and Woody et al., J. AIDS 2014 indicating that MAT, such as buprenorphine and methadone is effective in preventing HCV, less than 30% of patients in Opioid Treatment Programs in the US receive it.
A second factor contributing to the continued rise in HCV cases, is the HCV treatment gap. A study by Yehia BR et al, Plos One 2014; 9(7): e101554 showed that of the 3.5 million individuals diagnosed with chronic HCV infection, only 16% were prescribed HCV treatment. And of the total, only 9% achieved sustained virologic response (SVR), which is an undetectable HCV RNA level, 12 weeks after completion of therapy. NIDA has partnered with the CDC, the Appalachian Regional Commission, and SAMHSA to fund implementation research to improve these outcomes. The first FOA is: “HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the United States: Building Systems for Prevention, Treatment & Control (UG3/UH3): RFA-DA-17-014. This RFA seeks to fund two stage, multi-method research projects that inform community response and promote comprehensive, integrated approaches to prevent HIV and HCV infection, along with associated comorbidities, among IDUs in rural US communities. The second FOA is “Hepatitis C Virus (HCV) Advanced Molecular Detection in Support of Systems for Prevention, Treatment and Control of HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the U.S. (U24): RFA-DA-17-023. This is to support a Center for HCV next-generation sequencing using Global Hepatitis Outbreak and Surveillance Technology (GHOST) in Collaboration with CDC. The GHOST Center will support HCV next-generation sequencing activities of research projects funded by the companion RFA (RFA-DA-17-014).
Dr. Volkow then spoke about the many events centering on the opioid crisis, highlighting the National Prescription Drug Abuse and Heroin Summit that took place April 17-20, 2017 in Atlanta, Georgia. Some of the featured speakers included Dr. Thomas Price, Secretary of the U.S. Department of Health and Human Services, the former Surgeon General, Dr. Vivek Murthy, and the NIH Director, Dr. Francis Collins. Secretary Price announced $485 million in grants to fund evidence-based prevention and treatment to address the opioid abuse crisis. These grants will compliment funds under the Comprehensive Addiction and Recovery Act, which was approved in July 2016. Funds will be followed next year by another half-billion dollars based upon an HHS assessment regarding where the funds can be the most successful. He also relayed HHS’ top five priorities in addressing the opioid epidemic, which are: 1) Expanding access to treatment and recovery services; 2) Supporting the use of opioid overdose reversal drugs; 3) Improving public health surveillance to increase understanding of the epidemic; 4) Supporting research on pain and addiction; and 5) Advancing best practices for safe and effective pain management.
Lastly, Dr. Volkow shared a slide on an HBO special documentary that portrays an emotional description of the consequences of opioid addiction through the eyes of families who have lost loved ones, or who are still struggling to help family members. NIDA has been working with HBO on this hour-long documentary, and has partnered with them on building an online resource page to offer more information on MAT and evidence based treatment. The documentary “Warning: This Drug May Kill You” premiered May 1, 2017 at 10 p.m.
Council thanked Dr. Volkow for her presentation. A few council members brought up the need for more prevention research, including alternative pain management strategies, and increased influence and support for the prevention of opioid misuse and addiction. Dr. Volkow assured them that NIDA, through the ABCD study, along with private-public partnerships is working on prevention research. She also focused on this topic at various national scientific conferences and in working with HHS leadership. Council also applauded NIDA on its support of policy research in both areas of opioid use, as well as marijuana legalization.
Briefing on NASEM Marijuana Report: Background, Methods & Therapeutic Benefits – Sean Hennessy, Pharm.D., Ph.D., Professor of Epidemiology in Biostatistics and Epidemiology, University of Pennsylvania
Dr. Hennessy, an epidemiologist and pharmacologist at the University of Pennsylvania, and Dr. Sachin Patel, presented The National Academies of Sciences, Engineering, and Medicine (NASEM) Report on the Health Effects of Cannabis and Cannabinoids: Current State of Evidence and Recommendations for Research. Dr. Hennessy began his presentation with an overview of the study context and Statement of Task. The Task was to develop a comprehensive, in-depth review of existing evidence regarding the health effects (both harms and benefits) of cannabis and cannabinoid use, and to make short- and long-term recommendations regarding a research agenda.
He continued by listing the many study sponsors, including NIDA, the National Cancer Institute (NCI), the Centers for Disease Control and Prevention (CDC), as well as many other state governments and private organizations. He also provided a list of the committee members who had expertise in epidemiology, immunology, substance abuse, pharmacology, public health, and systematic review methodology, among others. The study approach adopted key features of a systematic review process in which the committee conducted an extensive review of relevant databases (e.g., Medline, Embase, the Cochrane Database of Systematic reviews, PsycINFO), with the initial search resulting in more than 24,000 articles. The committee considered more than 10,000 abstracts to determine relevance for the report. Primacy was given to recently published systematic reviews and high-quality research that studied one or more of the committee’s eleven prioritized health endpoints. These eleven health endpoints are: therapeutic effects, cancer incidence, cardio metabolic risk, respiratory disease, immune function, injury and death, psychosocial outcomes, mental health, problem cannabis use, cannabis use and abuse of other substances, and pre-, peri- and post-natal outcomes. Standardized language was applied to categorize the weight of evidence, and the evidence was labeled for each conclusion as either conclusive, substantial, moderate, limited, or no or insufficient.
There were special considerations in the study process. In terms of biological plausibility or mechanistic effects, the committee chose not to review basic, non-human research. Instead, they focused on identifying high quality studies in humans with the best information and lowest risk of bias to ensure that report findings and conclusions were as informative and relevant as possible. Synthesis of observational studies presented some challenges arising, in part, from the greater variability in study designs, and limitations in exposure measurements and reporting standards. Different health endpoints are discussed in each chapter of the report. The conclusions differ because of the study designs of the reviewed evidence, differences in characteristics of cannabis or cannabinoid exposure (e.g., form, dose, frequency of use), and the populations studied. This report was not designed to reconcile the proposed harms and benefits of cannabis or cannabinoid use across chapters. The committee formulated nearly 100 different research conclusions. For the sake of time, Dr. Hennessey reviewed a few selected chapter highlights.
He presented the potential therapeutic benefits of cannabis and cannabis-based products. In adults with chemotherapy induced nausea and vomiting, oral cannabinoids are effective anti-emetics; in adults with chronic pain, patients who were treated with cannabis or cannabinoids were more likely to experience a clinically significant reduction in pain symptoms; in adults with multiple sclerosis (MS) related spasticity, short-term use of oral cannabinoids improved patient-reported spasticity symptoms; and for these conditions the effects of cannabinoids were modest; for all other conditions evaluated there was inadequate information to assess their effects.
Dr. Sachin Patel to present the remainder of the report.
Adverse Effects and Recommendations
Sachin Patel, M.D., Ph.D.
James G. Blakemore Chair and Associate
Professor of Psychiatry & Behavioral
Sciences; Associate Professor of Molecular
Physiology & Biophysics & Pharmacology,
Dr. Patel continued by presenting the results of the data collected on adverse health effects, beginning with respiratory disease. There is substantial evidence of a statistical association between long-term cannabis smoking and worse respiratory symptoms, including more frequent chronic bronchitis episodes. In addition, there is moderate evidence of a statistical association between cessation of cannabis smoking and improvements in respiratory symptoms. There is limited evidence of a statistical association between occasional cannabis smoking and an increased risk of developing chronic obstructive pulmonary disease (COPD) when controlled for tobacco use. There is insufficient evidence to support or refute a statistical association between cannabis smoking and hospital admission for COPD. And there is insufficient evidence to support or refute a statistical association between cannabis smoking and asthma development or asthma exacerbation.
Dr. Patel then proceeded to discuss the effects of cannabis on cancer. There is modest evidence of no statistical association between cannabis smoking and the incidence of lung cancer. There is moderate evidence of no statistical association between cannabis use and the incidence of head and neck cancers. There is limited evidence of a statistical association between current, frequent, or chronic cannabis smoking and non-seminoma-type testicular germ cell tumors. There is insufficient evidence to support or refute a statistical association between cannabis smoking and the incidence of esophageal cancer. There is insufficient evidence to support or refute a statistical association between cannabis use and the incidence of prostate cancer, cervical cancer, malignant gliomas, non-Hodgkin lymphoma, penile cancer, anal cancer, Kaposi’s sarcoma, or bladder cancer. And finally, there is insufficient evidence to support or refute a statistical association between parental cannabis use and a subsequent risk of developing acute myeloid leukemia/acute non-lymphoblastic leukemia, acute lymphoblastic leukemia, rhabdomyosarcoma, astrocytoma, or neuroblastoma in offspring.
Regarding injury and death: cannabis use prior to driving increases the risk of being involved in a motor vehicle accident. In states where cannabis use is legal, there is increased risk of unintentional cannabis overdose injuries among children. It is, however, unclear whether and how cannabis use is associated with all-cause mortality or with occupational injury.
Moving on to the effects of cannabis use on the immune system, there exists a paucity of data on the effects of cannabis or cannabinoid-based therapeutics on the human immune system. There is insufficient data to draw overarching conclusions concerning the effects of cannabis smoke or cannabinoids on immune competence. There is limited evidence to suggest that regular exposure to cannabis smoke may have anti-inflammatory activity. There is insufficient evidence to support or refute a statistical association between cannabis or cannabinoid use and adverse effects on immune status in individuals with HIV.
He then presented the effects of cannabis use on prenatal, perinatal, and neonatal outcomes. Smoking cannabis during pregnancy is linked to lower birth weight in infants. The relationship between smoking cannabis during pregnancy and other pregnancy and childhood outcomes is unclear. As far as its effects on psychosocial outcomes, recent cannabis use impairs the performance in cognitive domains of learning, memory, and attention. Recent use may be defined as cannabis use within 24 hours of evaluation. A limited number of studies suggest that there are impairments in cognitive domains of learning, memory, and attention in individuals who have stopped smoking cannabis. And cannabis use during adolescence is related to impairments in subsequent academic achievement and education, employment and income, and social relationships and social roles.
Dr. Patel moved on to effects on mental health. There is substantial evidence of a statistical association between cannabis use and the development of schizophrenia or other psychoses, with the highest risk among the most frequent users. In individuals with schizophrenia and other psychoses, a history of cannabis use may be linked to better performance on learning and memory tasks. Cannabis use does not appear to increase the likelihood of developing depression, anxiety, and posttraumatic stress disorder. For individuals diagnosed with bipolar disorders, near daily cannabis use may be linked to greater symptoms of bipolar disorder than non-users. Heavy cannabis users are more likely to report thoughts of suicide than non-users. And regular cannabis use is likely to increase the risk of developing social anxiety disorder. Greater frequency of cannabis use increases the likelihood of developing problem cannabis use, and initiating cannabis use at a younger age increases the likelihood of developing problem cannabis use.
Finally, he discussed the results of the study as they relate to cannabis use and abuse of other substances. There is limited evidence of a statistical association between cannabis use and the initiation of tobacco use. There is limited evidence of a statistical association between cannabis use and changes in the rates and use patterns of other licit and illicit substances. And there is moderate evidence of a statistical association between cannabis use and the development of substance dependence and/or a substance abuse disorder for substances including, alcohol, tobacco, and other illicit drugs.
Dr. Patel discussed some of the barriers to cannabis research, such as regulatory barriers, including the classification of cannabis as a Schedule I substance, that impede the advancement of cannabis and cannabinoid research. It is often difficult for researchers to gain access to the quantity, quality, and type of cannabis product necessary to address specific research questions on the health effects of cannabis use. A diverse network of funders is needed to support cannabis and cannabinoid research that explores the beneficial and harmful health effects of cannabis use. And, in order to develop conclusive evidence for the effects of cannabis use on short- and long-term health outcomes, improvements and standardization in research methodology (including those used in controlled trials and observational studies) are needed.
Dr. Patel concluded his presentation by sharing the four report recommendations. Recommendation 1: Address Research Gaps. Develop a comprehensive evidence base on the short- and long-term health effects of cannabis use (both beneficial and harmful), with public agencies, philanthropic and professional organizations, private companies, and clinical and public health research groups providing funding. Prioritized research streams and objectives should include, but need not be limited to: clinical and observational research; health policy and health economics research; and public health and public safety research. Recommendation 2: Improve Research Quality. To promote the development of conclusive evidence on the short- and long-term health effects of cannabis use (both beneficial and harmful), agencies of the HHS, including NIH and CDC, should jointly fund a workshop to develop a set of research standards and benchmarks to guide and ensure the production of high-quality cannabis research. Recommendation 3: Improve Surveillance Capacity. To ensure that sufficient data are available to inform research on the short- and long-term health effects of cannabis use (both beneficial and harmful), the CDC, the Substance Abuse and Mental Health Services Administration, the Association of State and Territorial Health Officials, the National Association of County and City Health Officials, the Association of Public Health Laboratories, and state and local public health departments should fund and support improvements to federal and state public health surveillance systems. Recommendation 4: Address Research Barriers. The CDC, NIH, Food and Drug Administration, industry groups, and nongovernmental organizations should fund the convening of a committee of experts tasked to produce an objective and evidence-based report that fully characterizes the impacts of regulatory barriers to cannabis research and propose strategies for developing the resources and infrastructure necessary to conduct a comprehensive cannabis research agenda.
Dr. Volkow and Council members thanked both Drs. Hennessey and Patel for their presentations. Council had many questions regarding statistical associations vs. significance, and the quality of the studies. Council, along with Dr. Volkow verbalized that they agree with the NASEM recommendation to form a committee to help tackle the issue of regulatory and research barriers.
The Biomedical Research Workforce: Supporting More Investigators Sustainably and Efficiently – Michael Lauer, M.D., Deputy Director, Office of Extramural Research, NIH, and Jon Lorsch, Ph.D., Director, NIGMS
Dr. Lauer began by discussing a paper published by Bruce Alberts et al. “Rescuing US biomedical research from its systemic flaws.” PNAS 2014; 111:5773-7. It states, “the erroneous assumption of never-ending rapid growth has created an unsustainable hypercompetitive system that is discouraging even the most outstanding prospective students from entering our profession—and making it difficult for seasoned investigators to produce their best work. This is a recipe for long-term decline.” In addition, another group from the University of Wisconsin, led by Judith Kimble set up a series of workshops to identify problems in biomedical research and find strategies to rescue biomedical research in the US. The two core problems they identified were: too many researchers vying for too few dollars; and too many postdocs competing for too few positions.
This led Dr. Lauer, along with the Director of the National Institute of General Medical Sciences (NIGMS), Dr. Jon Lorsch to form and co-chair the Efficiency and Sustainability of Funding Policies Working Group of the Extramural Activities Working Group (EAWG) at NIH. One of the questions that Dr. Lorsch raised in an article he published “Maximizing the return on taxpayers’ investments in fundamental biomedical research.” Mol Biol Cell 2015; 26: 1578-82 was about changing the NIH funding metric. He asked “a question that at first glance may seem trivial but is, I believe, a significant one is whether our key metric for how…we invest in… research should be the number of grants we award or the number of investigators we support.”
One of the first tasks they took on was analyzing the number of NIH applicants vs. the number of awardees from 2003 to 2015. The number of awardees, unique scientists who serve as principal investigators (PIs) on at least one NIH research project grant (RPG), was about 25,500 in 2003, and it increased slightly to 28,000 in 2015. However, the number of unique applicants to the NIH during those years increased from approximately 60,000 in 2003 to 90,000 in 2015. This is what hyper-competition is, and he showed a graphic depicting hyper-competition.
Further evaluation of the biomedical research workforce age distribution of NIH PIs and medical school faculty from 1980-2010, showed that the mode is around 40 years of age for both PIs and AAMC faculty. However, there is a large gap of early stage investigators who are not being supported by R01s. This issue was addressed in a paper by David M. Blau and Bruce A. Weinberg, “Why the US science and engineering workforce is aging rapidly.” PNAS 2017; 114 (15): 3879-3884. In it they looked at data from the National Science Foundation, and from the U.S. Census, among other sources. The conclusion was that “the scientific work force has aged rapidly in recent years relative to the work force as a whole; the main causes have been a decline in the retirement rate of older scientists, which occurred after the elimination of mandatory retirement in universities and a convergence… as the baby boom cohort has aged; current trends imply a further substantial increase in the age of scientific workforce in coming years.”
NHLBI’s Marc Charette conducted further analysis of career stage by fiscal year from 1990 through 2015 for RPGs and other select activities. His analysis shows that in 1990 approximately 50% of the NIH funded investigators were early stage (age 45 or less), and it steadily decreased until 2007 when the ESI policy was implemented and the numbers stabilized. For scientists between the ages of 46-60 years, the numbers increased to about 50%, but have been steadily decreasing since 2005. The late stage investigators (age 60 year or greater) have been on the rise since 2005 to over 20% in 2015. With this information on hyper-competition adversely affecting early- and mid-stage investigators, as well as concerns and data indicating that output per dollar diminishes after a certain point, the working group considered whether research enterprise is working as effectively and efficiently as it could.
First, the working group had to find the appropriate tools to measure input. Dollars, percent effort, and grant counts are not consistent across field and are difficult to measure. Thus, they came up with a new tool, the Research Commitment Index (RCI). The RCI is a measure of a PI’s committed bandwidth that benchmarks the standard R01 grant to seven points, and gives other mechanisms a higher or lower score depending on the grant type. An analysis of the RCI total point distribution in FY 2015 for RPG and selected other activities, showed that the majority of NIH funded PIs had an RCI total points of 8, which indicates having only 1 R01 award, or equivalent. Further examination showed that the mean RCI from 1990 to 2015 for 98,656 unique investigators, excluding ARRA awards, was approximately 10. A dramatic change occurred in the pattern of grant distribution beginning in 1996, coincident with the beginning of the doubling and the end of mandatory retirement.
Second, they examined tools to measure output and impact of research. One of the tools, is the relative citation ratio. The NIH Office of Portfolio Analysis (OPA) looked at the weighted relative citation ratio per year to the total RPC research commitment index per year for 71,493 principal investigators funded from 1996-2014 with a median annual RCI of 7, and median funding years of 5. There was clear evidence of diminishing returns with increasing support (beyond an RCI of 20, the slope is essentially flat). Other outputs are mentorships, patents and guidelines. To assess this, George Santangelo and colleagues in OPA compiled a list of all successful and unsuccessful FY15-FY16 ESI applicants/awardees. They found that 58.9% of those ESIs are linked to at least one mentor who is currently funded by one or more NIH RPG awards. It turned out that parsing bio-sketches was an efficient way to establish the necessary data linkage; thus, they extracted the references from the bio-sketch of each ESI (RPG applicant) in FY15-FY16, and then identified mentors as NIH (RPG) awardees in FY15-FY16 who were last author on at least two of each ESI's papers as listed in their bio-sketch (the disambiguation needed to complete this step is relatively straightforward). The results: ESIs who are successful at obtaining an NIH RPG are no more likely to come from well-funded labs than less well-funded labs.
Dr. Lauer suggested that there may be opportunities to fund more investigators, even within the constrained resources that NIH has, that might increase the overall productivity of the system. A wise investment strategy might be to invest in as many scientists as possible to maximize the likelihood of great discoveries. He concluded his presentation by summarizing the current state of having an unstable system with hyper-competition that is adversely affecting early- and mid-career faculty. The system is inefficient, and may be adversely affected by diminishing returns. NIH is searching for ways to fund more investigators, especially in their early and mid-career, and are considering the tools for measuring input and output as described in this discussion.
Dr. Volkow and Council members thanked Dr. Lauer for his presentation. Council engaged in a discussion and brought up many questions related to the metrics used to determine the RCI, such as weighting senior authorship in publications, and data sharing as possible measures. Other suggestions were in terms of looking at the dilemma of hyper-competition as an opportunity to politically lobby for more funding, rather than reallocating fixed funds from senior researchers to young investigators. And, expanding the evaluation of mentorship as an outcome beyond just RPG funding.
Concept Clearances – NIDA Staff
Four total concepts received Council clearance.
Shoshana Kahana, Ph.D., Acting Deputy Branch Chief, Services Research Branch, DESPR, NIDA presented on behalf of Dr. Richard Jenkins on: Improving implementation of seek, test, treat and retain for people who inject drugs (PWID) in international settings. PWID continue to have HIV incidence and prevalence rates above the national average in many places throughout the world. National responses to PWID often are weak and usually lag responses among other populations. Similarly, PWID engagement in HIV care generally lags behind other key populations as well as the larger population of people living with HIV. Even in some “general population epidemic” countries, HIV disparities among PWID can limit the overall success of the UNAIDS 90-90-90 strategy. Seek, test, treat, and retain strategies need to be implemented in all key populations, including PWID in order to succeed. Service integration is needed in affected countries, including integration of HIV prevention and treatment for PWID and integration of drug use and HIV services; along with attention to polysubstance use among PWID. This requires better models for program implementation and efforts to increase the implementation capacity of national HIV/AIDS programs among drug users.
This concept would support developing and testing implementation models that can be scaled-up in affected countries. Sustainable programs will need to align with national HIV/AIDS plans and provide models for large scale implementation, including QA/QC systems. This effort would include collaboration with national HIV/AIDS programs as well as major donors such as PEPFAR and Global Fund, which have platforms for reaching PWID and provide access to local epidemiology and services data. PEPFAR’s implementing partners include SAMHSA which provides specific substance use technical assistance in a number of countries. New donor programs include syringe services and drug treatment settings that can be leveraged to provide or actively link to additional HIV and substance use services. Some countries are developing new health financing systems that also can be leveraged to expand HIV prevention and treatment for PWID. In addition, projects would be encouraged to make use of existing NIH initiatives such as NIDA-funded researcher networks and IeDEA (NIH’s cohort of cohorts co-funded by NIDA) which provides clinical cohort platforms that can be leveraged for new research.
Dr. Kahana, presented a second concept as well: Pre-exposure prophylaxis for HIV prevention and treatment of substance using populations. Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months. The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir). The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013). Consequently, the actual efficacy of PreP for active injectors, adherent methadone users, or even non-injectors who actively use opiates and other drugs is unknown.
NIDA has not funded much research on the several key question related to PreP use among substance-using populations The primary goal of this initiative is to examine the role of PreP in substance use and HIV trajectories and or treatments, including:
—To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?
—To what degree does substance use affect access and adherence to PreP?
—How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
Oliver Berton, Ph.D., Program Officer, BRAIN, Division of Neuroscience and Behavior presented on “tools to enhance studies of non-neuronal cells in the brain.” Glial and vascular cell populations, which represent more than half of all the cells in the brain, remain largely understudied by neuroscientists, in large part due to a lack of adapted tools. The goal of this initiative (managed by NIDA for the BRAIN initiative) is to encourage research that develops cutting edge technologies tailored to study individual or defined groups of non-neuronal cells and disseminate them to the broad neuroscience community.
Glia represent the largest non-neuronal cell population in the nervous system, comprising astrocytes, oligodendrocytes, microglia, ependymocytes, radial glia, and NG2 cells. Cerebral vascular cells constitute the other major class of nonneuronal cells, which includes endothelial cells, smooth muscle and pericytes. Non-neuronal cells and their interactions with neurons play pivotal roles in various functions including, but not limited to, the formation and maintenance of the Blood Brain Barrier (BBB), metabolic coupling, the regulation of cerebral oxygenation and blood flow (basis for BOLD signal), circuit development, synaptic plasticity and neuronal repair. Systematic studies of neuro‐glio‐vascular interactions across brain regions, developmental periods and physiological contexts such as drug abuse are scarce. These studies require new genetic and non-genetic tools for delivering genes, proteins and chemicals to non-neuronal cells of interest and restricting genetic access to a specific developmental period and/or to specific microdomains in the nervous system, with greater precision and sensitivity.
Research supported by this initiative will provide new tools for identifying and classifying non-neuronal cells and manipulating and monitoring their specialized functions, based on their molecular heterogeneity, developmental stage or functional state, and allow investigation of their contribution to normal and abnormal neural network function. Plans for validating these tools/technologies and benchmarking them against existing approaches will be an essential feature of a successful application. Tools that can be used in several species/model organisms rather than in a single species will be sought.
These research areas could be explored using fresh accessible tissues or post-mortem tissues including brain. Ultimately this research will yield foundational knowledge that will help inform the development of a future HIV cure for patients with SUDs.
John Satterlee, Ph.D., DNB Coordinator for Trans-NIH Programs and Activities, Division of Neuroscience and Behavior presented his concept ‘Exploiting HIV/Host genomic information to understand HIV compartments in substance using populations. Upon cellular infection, the approximately 10,000 nucleotide HIV RNA genome is copied into complementary DNA (cDNA) by an error prone reverse transcriptase. The other strand of the cDNA is then synthesized and the double-stranded HIV genomic DNA is integrated into the host cell genome where it either remains dormant or is transcribed into new HIV RNA genomes. During this process, a reverse transcription error or mutation in an HIV DNA genome that is latently integrated into the host genome is “frozen in time.” This DNA sequence information can be used to investigate HIV compartment formation and latent reactivation.
Additionally, chromatin architecture assays indicate that the HIV DNA genome tends to integrate into host chromatin near the nuclear pore. However, there is much that we do not understand about HIV integration sites and how they may differ between types of HIV-infectable cells.
This initiative will support exploratory and hypothesis-driven research projects that:
—Exploit integrated HIV genomic sequences to better understand how founder HIV seeds cellular compartments over time in individuals with and without substance use disorders (SUDs); or
—Explore how substance use and/or suboptimal antiretroviral therapy adherence impacts reactivation of latent HIV in cellular compartments; or
—Exploit epigenomic or chromatin architecture assays to investigate factors that influence the sites of HIV integration within the host genome in different cellular compartments and how substance use influences these factors.
This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):
Reducing Incidence of HIV/AIDS, including: developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services. Next generation of HIV therapies with better safety and ease of use including: developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses. Where does PreP fit within a comprehensive program for prevention of HIV acquisition?
The 126th meeting of the National Advisory Council on Drug Abuse was adjourned at 4:17 p.m.
I hereby certify that the foregoing minutes are accurate and complete.
Nora D. Volkow, M.D.
National Advisory Council on Drug Abuse
Susan Weiss, Ph.D.
National Advisory Council on Drug Abuse
Note: Informational materials provided to the public at the open session of the meeting may be obtained from the Executive Secretary.